Folic acid and various kinds of folic acid derivatives are commonly used as parts of different cancer treatments.
For example, leucovorin (folinic acid, LV) or its levo-isomer, levoleucovorin, and also other reduced folates, are frequently used in combination with fluorouracil (5-FU) in order to increase the anti-tumoral effect in treatment of patients with colorectal cancer. 5-FU+LV (FLV) treatment may be used alone or in combination with oxaliplatin or irinotecan as adjuvant as well as palliative treatment of colorectal cancer. Leucovorin or levoleucovorin is also used in combination with methotrexate as a “rescue agent” in order to reduce side effects of the methotrexate.
[6R]-5,10-methylenetetrahydrofolate (6R-methylenetetrahydrofolate, [6R]-MTHF, Modufolin®) is an endogenous folate metabolite now being developed for direct administration to patients with the aim to increase the efficacy and decrease the side effects of chemotherapeutic agents used in the treatment of solid tumors. It has been suggested that the use of the endogenous folate [6R]-MTHF in cancer treatment is more favourable than the use of other folic acid derivatives, e.g. leucovorin, since [6R]-MTHF is the active agent resulting from folate metabolism. In particular, it has been suggested that the administration of e.g. leucovorin is less efficient than the administration of [6R]-MTHF, since many metabolic steps are required in order to achieve the active species, i.e. [6R]-MTHF, from leucovorin. In practice, it has been seen that some patients nevertheless benefit from the administration of leucovorin as a part of cancer treatment, while in other patients, the positive effects can hardly be seen at all. The same is true for e.g. folic acid and levoleucovorin.
To date, the mechanisms underlying a successful folate treatment as part of a cancer treatment have not been resolved. The routine treatments involving e.g. folic acid, levoleucovorin or leucovorin are therefore frequently used for all patients, although this means that these substances are sometimes administered to patients as part of a cancer treatment without giving rise to any positive effects. This is not satisfactory in terms of any risks associated with the administration of unnecessary, non-active substances to patients, and also not in terms of cost efficiency. Furthermore, it is not satisfactory that the positive synergistic effects of the folate treatment, e.g. the increased anti-tumoral effect, do not appear in some patients. Neither is it satisfactory that the mediation of toxicity is difficult to predict or expect with certainty. There is thus a need in the art for a more predictable use of folic acid and folic acid derivatives in cancer treatment.